Methods for producing muscle relaxant and cns-depressant effects with 3-amino-4-phenyl furazan and composition therefor

ABSTRACT

METHODS AND COMPOSITIONS FOR PRODUCING ANTI-CONVULSIVE, MUSCLE-RELAXING, AND CNS-DEPRESSING EFFECTS IN MAMMALS, BY ADMINISTRATION OF AN EFFECTIVE AMOUNT OF 3AMINO-4-PHENYL-FURAZAN.

United States Patent 3,577,544 METHODS FOR PRODUCING MUSCLE RELAXANT AND CNS-DEPRESSANT EFFECTS WITH 3- AMINO-4-PHENYL FURAZAN AND COMPOSI- TION THEREFOR Claude Lehmann and Ernst Renk, Basel, Switzerland, assignors to Geigy Chemical Corporation, Ardsley, N.Y. No Drawing. Filed Feb. 2, 1968, Ser. No. 702,550 Claims priority, application Svvgtzerland, Jan. 26, 1968,

3 Int. Cl. A61k 27/00 US. Cl. 424272 2 Claims ABSTRACT OF THE DISCLOSURE Methods and compositions for producing anti-convulsive, muscle-relaxing, and CNS-depressing effects in mammals, by administration of an eifective amount of 3- amino-4-phenyl-furazan.

DETAILED DISCLOSURE The present invention concerns a new method and a new agent for the tretament of pathologically increased muscle tone in mammals.

Surprisingly, it has been found that 3-amino-4-phenylfurazan is a good central muscle relaxant having a high therapeutic index. The active substance can be used, e.g. to relieve pathologically increased muscle tone caused by rheumatic diseases, fibrositis, bursitis, myositis, torticollis, spondylitis or disc lesions.

3-amino-4-phenyl-furazan itself and the production thereof have been described in the literature [cf. F. Angelico and S. Cusmano, Gazz. chim. ital. 66, 3-8 (1936), C. A. 30, 6366 (1966)].

The muscle relaxant effect is ascertained pharmacologically by various methods.

(a) Determination of the inhibition of the pinna and corneal reflexes:

A characteristic of the central muscle relaxants is the abolition of the pinna reflex after administration of fairly small quantities of active ingredient, whereas the corneal reflex can only be abolished after much higher dosage.

Procedure: The reflexes are determined in white mice weighing 18-25 g. The pinna reflex and the corneal reflex are tested by stroking the external auditory meatus or touching the cornea with a nylon brush. The dosage is determined at which the pinna reflex and the corneal reflex are abolished in 50% of the animals. The mice are not fed for 12 hours before the beginning of the test. The test substance is administered by mouth 1 hour before the test. The E.D. is ascertained by interpolation of the probability graph (Schleicher and Schiill No. 298 /2).

Results:

E.D. pinna-about 600 mg./kg. p.o. E.D. cornea- 1000 mg. p.o.

(b) Determination of the inhibition of the monosynaptic patellar tendon reflex and of the polysynaptic flexor reflex:

Procedure: Tracheotomy is performed on cats weighing 2.5-3.0 kg. under chloralose-urethane anaesthesia (chloralose 55 mg./kg. i.p. as a 3% solution in 20% urethane). The test substance in 5% propylene glycol solution is injected within 3 minutes into the jugular 'vein.

'PATELLAR TENDON REFLEX After the femur has been fixed, the contraction of the quadriceps femoris muscle of the right hind leg is induced by hitting the patellar tendon with an automatic hammer 3,577,544 Patented May 4, 1971 at 10 second intervals. The contraction is recorded isotonically. The maximum change in amplitude is determined as a percentage related to the amplitude of the muscle contractions before administration of the product.

FLEXOR REFLEX The contractions of the tibialis anterior muscle of the left hind leg are recorded isotonically after Submaximal electrical stimulation of the central section of the severed tibial nerve. Submaximal stimulation is effected with single rectangular current impulses (Grass stimulator, dura tion of stimulation: 2 m. sec., voltage 0.5-5.0 v.). The interval between two stimulations is 10 seconds. The maximum change in amplitude is determined in percent "ice (c) Determination of the anticonvulsant effect by means of electroshock in the rat (partial suppression).

Another characteristic property of the central muscle relaxants is their anticonvulsant effect. This effect of the test substance can be demonstrated, e.g. as follows:

Procedure: Male white rats weighing -150 g. are used for the test. The electrodes are applied to the external ears. An alternating current of 50 c./ s. of 100 v. is used for the electroshock and the stimulation lasts 0.63 second. The test substance is administered by mouth 1 hour before the electroshock. The dose which prevents tonic convulsions in the hind legs in 50% of the animals is ascertained by interpolation on the probability graph (Schleicher and Schiill No. 298 /2 (E.D.

Result: E.D. about 25 mg./kg. p.o.

The acute toxicity of the test compound is determined by a single administration by mouth in male and female mice. The observation period is 8 days. The L.D. is determined by interpolation on the probability graph (Schleicher and Schiill No. 298 /2 Result: Acute L.D. O mg./kg. p.o.

The acute toxicity is also tested in male and female rabbits weighing 1.5-2.0 kg. The test compound is administered i.e. in 5% solution in 100% propylene glycol. A speed of injection is 1 ml. in 30 seconds.

Result: Acute L.D. 1500 mg./kg. p.o.

The daily dosages of the active substance vary between 45 and 6000 mg. for adult patients of normal bodyweight. For children, dosages reduced according to their weight are administered. Suitable dosage units such as drages (sugar coated tablets), tablets, suppositories and ampoules, preferably contain 15-1000 mg. of the compound.

Dosage units for oral administration preferably contain between 60-90% of 3-amino-4-phenyl-furazan as active ingredient. To produce tablets or drage cores, the active substance is combined, e.g. with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, maize starch, potato starch, amylopectin, talcum, also laminaria powder or citrus pulp powder, optionally with the addition of lubricants and binders such as highly dispersed silicic acid, magnesium or calcium stearate, stearic acid, glycerin or polyethylene glycols or gelatin or cellulose derivatives such as ethyl cellulose and sodium salt of carboxymethyl cellulose. Drage cores are then coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents, e.g. shellac. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.

Other suitable dosage units for oral administration are hard gelatine capsules as well as soft capsules made of gelatine and a softener such as glycerin. The hard capsules preferably contain the active substance in the form of a granulate in admixture with diluents such as lactose, saccharose or maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilisers such as sodium metabisulphite (Na S O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols or oils, to which stabilisers can also be added. Dosage units which are also suitable for oral administration are, e.g. pastilles prepared with the usual additives.

Examples of dosage units for rectal administration are suppositories which consist of a combination of S-amino- 4-phenylfurazan with a suppository foundation, e.g. natural or synthetic triglycerides, or also gelatine rectal capsules which contain, e.'g. a combination of the active substance with polyethylene glycols or oils.

Dosage units for parenteral administration advantageously contain 110% of active substance, water and a solubility promoter or emulsifier. The following compounds, for example, can be used as solubility promoters or emulsifiers: propylene glycol, sodium benzoate or the sodium salt of a hydroxybenzoic acid, water soluble salts of bile acids such as sodium dehydrocholate, morpholine desoxycholate, ethanolamine cholate, inositol phosphatide preparations and lecithin preparations having a poor oil content, optionally together with partial glycerides of higher fatty acids such as monoor di-olein, and/or their polyoxyethylene derivatives.

The present invention relates to methods of treating convulsions, muscular stiflfness and mental disorders in mammals and to therapeutic composition for producing anticonvulsive, muscle-relaxing, and CNS-depressing effects comprising a pharmaceutical carrier and a therapeutically effective amount of 3-amino-4-phenyl furazan in dosage unit form acceptable for internal administration.

The following examples further illustrate the production of different forms for administration but they by no means limit the scope of the invention in any way.

EXAMPLE 1 To produce 100,000 tablets, each of which contains 500 mg. of active substance, 50.000 kg. of 3-amino-4-phenyl furazan are mixed with 2.000 kg. of dried potato starch. The mass obtained is moistened with 1.200 kg. of stearic acid in 4 litres of ethanol and the whole is mixed for minutes. 1.200 kg. of gelatine in 16 litres of distilled water are then added and the mass is kneeded for 20 minutes. As soon as it is sufficiently moist, it is granulated through a sieve mesh/sq. cm.) and dried. The dried granulate is again sieved (60 mesh/sq. cm.) and is 4 then mixed for 1 hour with 4.000 kg. of potato starch, 1.200 kg. of talcum and 0.400 kg. of sodium carboxymethyl cellulose. The mass obtained is pressed into tablets, each of which weighs 600 mg.

Example 2 To produce 100,000 drages, each of which contains 500 mg. of 3-amino-4-phenyl-furazan as active substance, 50.000 kg. of active substance are mixed with 3.700 kg. of lactose and 1.000 kg. of highly dispersed kieselguhr. The mixture is moistened with a granulating liquid heated to 50 C. consisting of 2.000 kg. of gelatine, 2.000 kg. of glycerin and 1.5 litres of water. The moist mixture is granulated through a suitable sieve (e.g. sieve III, Ph. Helv. V.). The granulate is then dried for 8 hours in a drying, oven at 40-50 C. or in a fluidised-bed drier for about 40 minutes at 40 C. and then sieved through a suitable sieve (e.g. sieve III-IIIa, Ph. Helv. V). The granulate is. then mixed with 3.000 kg. of talcum and 3.000 kg. of maize starch and 300' g. of magnesium stearate and the mixture is pressed into 1,000,000 drage cores each of which weights 6 50 mg.

Example 3 To produce 1,000 capsules each containing 500 mg. of active substance, 500.0 g. of 3-amino-4-phenyl-furazan are mixed with 25.0 g. of talcum and 10.0 g. of magnesium stearate and the mixture is sieved through a sieve (e.g. sieve IV, Ph. Helv. V) whereupon it is evenly filled into capsules of size 0.

Example 4 Suppositories are prepared by mixing 750 g. of 3- amino-4-pheny1 furazan with 2.250 kg. of adeps solidus and then forming 1000 suppositories of 3.0 g. of each containing 750 mg. of 3-amino-4-phenyl furazan.

What is claimed is:

1. A therapeutic composition for producing a muscle relaxing or central nervous system depressant effect comprising a pharmaceutical carrier and a therapeutically effective amount of 3-amino-4-phenyl furazan in a unit dosage form selected from the group consisting of a drage, tablet, capsule, pastille, suppository and ampoule.

2. The method of producing a muscle-relaxing or a central nervous system depressant effect in a mammal comprising administering to said mammal an effective amount of 3-amino-4-phenyl furazan.

P References Cited UNITED STATES PATENTS 3,338,899 8/1967 Didier et al. 424-272 3,279,988 10/ 1966 Buting et al. 424272 OTHER REFERENCES Chem. Absts. 53, pp. l8010 lll (1959).

STANLEY J. FRIEDMAN, Primary Examiner 

